The success of heart transplantation depends upon satisfactory function of the new heart after implantation in the recipient. One factor contributing to a successful transplant is heart preservation while it is ex vivo, that is while it is being transported from the donor to the recipient. It is rare, indeed, that a donor and recipient will be at the same medical facility. Therefore, the ability to preserve donor hearts while transporting them long distances is crucial to successful heart transplantations.
In recent years, extensive studies have been conducted toward extension of heart preservation. To date, however, preservation ability is on the order of four to five hours using cold ischemic preservation. Longer safe preservation times would greatly increase the number of potential donor hearts.
Moreover, open heart surgery has become a common major surgery in the western world. During this operation, the heart is disconnected from the blood supply (i.e, under ischemia). In order to be preserved during the operation, a cold cardioplegic solution is infused into the heart. However, to date, this preservation is limited to about two hours before irreversible damage to the heart is caused.
During the past decade, St. Thomas' Hospital (ST) cardioplegic solution has been used routinely in heart transplantation programs and in open heart surgery.
It was recently shown that under hypothermic ischemic conditions (hypothermic condition without any infusion of perfusate), myocardial intracellular concentration of Na.sup.+ is markedly increased. (Askenasy et al , "Sodium ion transport in rat hearts during cold ischemic storage", Magn. Reson. Med., 1992, 28:249-263; Pike et al., ".sup.23 Na NMR measurements of intracellular sodium in intact perfused ferret hearts during ischemia and reperfusion", Am. J. Physiol, 1990, 259:H1767-H1773; and Pike et al , ".sup.23 Na and .sup.39 K nuclear magnetic resonance studies of perfused rat hearts", Biophys J., 1985, 48:159-173). This intracellular Na.sup.+ accumulation may lead to intracellular accumulation of water, followed by an increase in cell volume and mitochondrial swelling and to an increase in intracellular Ca.sup.++ concentration via the Na.sup.+ /Ca.sup.++ exchanger and eventually to cell death.
Furosemide is a loop diuretic agent, commonly used in the treatment of hypertensive patients. A diuretic is a substance that increases the rate of urine output. Most diuretics act by decreasing the rate of reabsorption of fluid from the tubules, reducing the total amount of fluid in the body. The loop diuretic agents are known to block the Na.sup.+ /K.sup.+ /Cl.sup.- co-transporter, and called such because they were first discovered as blockers of the reabsorption of sodium and chloride ions from the ascending limb in the loop of Henle in the kidney.
Applicants discovered that under hypothermic conditions, as in the hypothermic preservation of the heart, the Na.sup.+ /K.sup.+ /Cl.sup.- co-transporter located in the sarcolemma (Geck et al., "The Na-K-2Cl Contrasport system", Journal Membrane Biol., 1986, 91:97-105) plays a major role. Due to the decrease in temperature and the lack of energy supply, the Na/K ATPase is inactive causing a large amount of Na+to permeate into the cell. This intracellular accumulation of Na.sup.+ can be markedly blocked by the administration of the Na.sup.+ /K.sup.+ /Cl.sup.- blockers, such as furosemide, bumetanide, or piretanide, protecting the myocardial tissue during the preservation time.